Gray 2017.

Methods	Multisite, double‐blind randomised, placebo‐controlled trial
Participants	Setting: outpatient, 6 sites within the National Drug Abuse Treatment Clinical Trials Network, USA. Scheduled duration 12 weeks Participants: 302 adults aged 18–50 years, seeking treatment, cannabis dependent by DSM‐IV‐TR and positive urine test during the initial screening visit Group sizes: group 1, 153; group 2, 149 Groups similar on demographics and baseline clinical characteristics, except employment (group 1, 42.5%; group 2, 60.4% working) and education (group 1, 28.5%; group 2, 14.8% graduated from high school) Mean age 30.3 years 71.5% male 58.3% white Mean cannabis use 26.0/30 days at baseline. Exclusion criteria: unstable psychiatric conditions, dependence on substances other than cannabis or tobacco, recent synthetic cannabinoid use
Interventions	Group 1: N‐acetylcysteine, 1200 mg twice daily Group 2: placebo All participants received contingency management and medical management
Outcomes	Odds of negative urine cannabinoid tests during treatment Cannabis urine screens by central laboratory during weekly clinic visits and at post‐treatment follow‐up Adverse effects at each study visit Adherence defined as taking ≥ 80% of prescribed medication each study week, confirmed by riboflavin level
Notes	Funding: research grants (US National Institutes of Health) 5/23 authors declared research support, or unrestricted grants from pharmaceutical companies, or the provision of advisory and consultancy services to pharmaceutical companies, none of which were involved in this trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Randomization, conducted centrally through the CTN Data and Statistics Center, was on a 1:1 ratio, with stratification by study site and self‐reported binary tobacco smoking status."
Allocation concealment (selection bias)	Low risk	Quote: "Randomization, conducted centrally through the CTN Data and Statistics Center;" "United States Pharmacopeia grade NAC [N‐acetylcysteine] powder was encapsulated in 600 mg quantities (two 600 mg capsules per twice‐daily dose). Matched placebo capsules were also prepared."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "Among participants assigned to NAC, 46.5% guessed they were receiving NAC and 53.5% guessed they were receiving placebo, and the medical clinician guessed that 52% were receiving NAC and 48% were receiving placebo. Among those assigned to placebo, 53.7% guessed they were receiving NAC and 46.3% guessed they were receiving placebo, and the medical clinician guessed that 57.3% were receiving NAC and 42.7% were receiving placebo. These differences were not statistically significant, and the participant and medical clinician agreed on guesses more often than by chance (p < 0.0001)."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	As indicated above, participant may have been able to accurately guess their group allocation, but the outcomes reported were objective in nature and these are less likely to be affected if the blind is broken.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Retention rates and data availability similar in the 2 groups Missing urine tests imputed as positive
Selective reporting (reporting bias)	Low risk	Published protocol, reported outcomes consistent with protocol
Other bias	Low risk	Riboflavin added to all capsules as a biomarker for medication adherence. Criteria defining adherence specified in advance. Analyses comparing outcomes for those meeting or not meeting these criteria were undertaken.